PROJECT SUMMARY Along with wisdom, age brings many unpleasant alterations in neural function: memory declines, reflexes and mobility deteriorate, and the brain becomes more susceptible to disease. Though these phenomena are well documented, little is known about their molecular bases. To elucidate the neurological alterations that occur with age, we have focused our studies on synapses of the visual system, which are amenable to high- resolution analysis and are a the site of significant age-related functional deterioration. In a recent study (Samuel et al. J. Neurosci. 2011), we found that as the retina ages, different neurons exhibit distinct morphologic changes to their neurite architecture and develop aberrant connections with their synaptic partners. Preliminary studies suggest that these changes are accompanied by, and may result from, dysregulation of a specific serine/threonine kinase, LKB1. LKB1 is a central modulator of cellular metabolism and phosphorylates and activates the energy sensor AMPK. We find that old retina neurons show markedly reduced activation of AMPK coincident with high levels of neuronal miswring. Moreover, deletion of LKB1 in young animal leads to outer retina rewiring phenotypically identical to that observed in aged animals. Therefore, interventions that preserve or restore the LKB1-AMPK pathway may prevent age-related changes in neuron connectivity. I now propose a set of studies designed to examine the molecular mechanisms by which the LKB1 energy homeostasis pathway modulates neuronal aging and identity new synaptic aging genes. Specifically, I will: (1) dissect the role of the LKB1-AMPK pathway in outer retina miswiring; (2) determine the mechanisms by which these signaling networks modulate this process; and (3) expand these analyses to synaptic aging of centrally projecting ganglion cells. In parallel, I will perform transcriptional profiling of neuron subsets that miswire in order to identify additional molecular correlates of age-related neuronal decline. These studies will define the role of energy misregulation in synaptic aging and may identify pathways that affect both cognitive maintenance and age-related disease susceptibility.